Heroin addiction is a growing health care problem in the United States. The United States Department of Health and Human Services' Substance Abuse Branch issued a report in December of 1994 stating that the number of emergency department visits directly related to heroin use rose from 48,000 in 1992 to 63,000 in 1993, a 31% increase. The rate of heroin-related episodes per 100,000 people rose 81%, from 15 to 28 per 100,000, between 1990 and 1993. Upon breaking down the heroin-using population into ethnic groups and age groups, it has been demonstrated that all subsets have increased rates of use for this time period.
Human opiate detoxification has been in use for some time. More than 31,000 individuals of the Empire Blue Cross and Blue Shield subscriber base in New York were hospitalized at least once for opiate dependency between 1982 and 1992. The majority of these individuals were working adults, and their principal reason for hospitalization was addiction treatment. Drug detoxification accounted for 96% of the admissions, and the length of stay ranged between five and ten days.
In cases where individuals have been recently "detoxed" there is a high incident of relapse and re-addiction. While these former addicts are often strongly motivated to seek treatment and relapses often produce quilt and depression, they are still unable to resist giving in to the intense craving for heroin or pressure from drug dealers.
In recognition of the foregoing, opiate antagonists have been administered to such detoxified addicts. Opiate antagonists are defined as chemical compounds which block the effects of opiate drugs by blocking the opiate receptors in a patient. By blocking the effects of agonist opiates, opiate antagonists also prevent the development of physical dependence and tolerance to opiate drugs, such as heroin.
It should be noted that while opiate antagonists do not produce symptoms when they are used in the treatment of heroin dependence, they will precipitate an abstinence syndrome in individuals who are physically dependent on an opiate drug. By virtue of their affinity for the opiate receptors, they will compete with and oftentimes displace opiate agonists from the receptor sites. Accordingly, a heroin addict must be detoxified before he can be treated with an opiate antagonist. Once completely free of opiate drugs, however, no symptoms will be produced by the administration of the opiate antagonist.
One preferred antagonist used in the treatment of former heroin addicts is naltrexone (N-cyclopropylmethylnoroxy morphone). Naltrexone, such as some opiate antagonists, provides no euphoric effects and there are no observable pharmacological consequences when a patient stops taking the drug. For naltrexone treatment to be effective, sufficient levels of the drug must be maintained in the patient for a substantial period of time. This typically requires the patient to self-administer dosages of the drug several times a week.
A major problem with the use of opiate antagonists, such as naltrexone, in the treatment of opiate addiction has been patient compliance. This is frequently due to the patient's strong desire to experience the euphoric feeling which would otherwise be prevented by the presence of the opiate antagonist in his or her bloodstream. Thus, it has been said that rehabilitation of the patient is the first target. (Brewer, Addiction Biology: 2, 291-303 (1997)).
One solution for improving patient compliance and concomitant rehabilitation is the time-lapsed release of an antagonist such as naltrexone over a desirably long period of time. Several methods for implantable antagonists in animals for purposes other than to successfully treat opiate-addicted humans have been reported. For example, in PECHNICK et al., Neuropharmacology, 26(11):1589-1593 (1987), male rats injected with pentobarbital showed sleeping time to be increasingly antagonized after naltrexone administration by injection, but not in subjects implanted with a pellet of naltrexone. This study concluded that potentiation of pentobarbital sleeping time produced by opiates is mediated by opiate receptors, but did not show any development of tolerance. No indication of how the naltrexone pellets are made or their composition is provided in this study, except that the naltrexone pellets were obtained from the National Institute on Drug Abuse. While no clinical treatment program for humans is suggested, the article concludes with suggestion that the use of barbiturates by individuals chronically using opiates may have profound adverse consequences.
In BARDO et al., Pharmacology, Biochemistry & Behavior, 28:267-273(1987), rats implanted with a naltrexone pellet were shown to be devoid of morphine-induced conditioned place preference (CPP). Pellets of naltrexone freebase used in this study were also obtained from the National Institute on Drug Abuse. Nothing is mentioned as to pellet composition or method of manufacture. It was concluded that chronic naltrexone exposure produces behavioral supersensitivity to morphine-induced reinforcement and hyperactivity, and that the reinforcing efficacy of heroin is potentiated following chronic naltrexone administration. It was also concluded that up-regulation of opiate receptors following chronic naltrexone enhances opiate reward and that chronic naltrexone also potentiated morphine-induced hyperactivity in rats.
BARDO et al., Neuropharmacology 27(11): 1103-1109 (1988) also discusses rats implanted with naltrexone pellets for short time intervals (from one to ten days in this study). As in other references pellets were obtained from the National Institute on Drug Abuse, but nothing is mentioned as to methods of pellet manufacture or pellet composition. As shown in this study, one-day after pellet removal naltrexone-treated animals displayed an enhanced response of the synthesis of dopamine (DA), and that naltrexone removal after ten days showed no effect on morphine-induced changes to DA synthesis and locomotor activity to indicate that supersensitivity to morphine is transient.
GREELY et al., Psychopharmacology, 96:36-39 (1988) also examined the effects of pellet implantation of opiate antagonists naloxone and naltrexone, and of chronic administration of naloxone by subcutaneous injections in rats. In this study, 50 mg pellets of naloxone and naltrexone were employed containing 10 mg naloxone or naltrexone as base (significantly low compared to human dosages of 1000 mg or more). Procedures for manufacturing these pellets or their exact composition were not revealed. The results of this study were said to show that repeated painful stimulation results in analgesia in rats treated with an opiate antagonist.
In YAMAGUCHI et al., Journal of Controlled Release, 19:299-314 (1992), a study was performed with subcutaneous implantation of naltrexone sustained release preparations such as naltrexone-containing beads and microspheres in rats and rabbits to evaluate tissue rejection. As in other references discussed herein, the beads and microspheres were obtained from the National Institute of Drug Abuse and are said to based on a matrix of poly-(L(+)-lactic-co-glycolic acid, a composition found unacceptable for use in humans by CHIANG, infra. This study concluded that all of the tested implantable materials caused inflammatory responses.
In another rat-based study, HEMENDRA et al., Gen. Pharmac., 25(1):149-155 (1994), showed the effects of pellets containing 10 or 30 mg of naltrexone base implanted for up to seven days on the development of tolerance and physical dependence on morphine in rats. Again, naltrexone pellets used in this study were obtained from the National Institute on Drug Abuse, but the reference is silent as to method for pellet production and composition. As concluded in this study, when left intact, naltrexone pellet implantation prevents naltrexone-induced decrease in body temperature, and increase in fecal and urinary output and inhibits body weight loss during abrupt withdrawal. The results are said to show that a single pellet of 10 mg of naltrexone can effectively block morphine tolerance and physical dependence in rats, and that such a procedure may be useful in studying biochemical, endocrinological, and immunological mechanisms involved in opiate addiction processes.
Other animal-based studies are REUNING et al., J. of Pharmakinetics and Biopharmaceutics, 11(4):369-387 (1983) (naltrexone-containing lactic acid/glycolic acid copolymer beads subcutaneously implanted in monkeys); SHARON et al., Research Monograph 28, National Institute on Drug Abuse (1980)(polylactic-co-glycolic acid bead-containing naltrexone implanted in mice); and HARRIGAN et al., Naltrexone Research Monograph 28, National Institute on Drug Abuse (1980) (naltrexone 75/25 dipalmitin/tripalmitin matrix rods, naltrexone/disodium carbonate/chronomer rods, and naltrexone lactic acid glycolic acid and copolymer beads implanted in monkeys).
None of the aforementioned studies, however, provide any teaching or guidance for the expectation of successful treatment of opiate-addicted humans with a subcutaneously implantable antagonist-containing pellet.
Indeed, studies undertaken with subcutaneous administration of naltrexone-containing beads in opiate-addicted humans have been shown to be unacceptable for clinical treatment. In CHIANG et al., "Clinical Evaluation of a Naltrexone Sustained-Release Preparation", Drug and Alcohol Dependence, 16:1-8 (1985), beads composed of copolymers of lactic acid and glycolic acids containing 70% naltrexone were administered (30 or more at a time) for periods of from 2-4 weeks in male humans. To minimize tissue reactions, the beads were dispersed in a circle of 2 inches in diameter of the implantation site. As concluded in this study, the results were thought to indicate that a sustained-release dosage which is capable of maintaining a constant naltrexone plasma level for one month can be clinically useful if sufficient plasma levels of naltrexone are sustained. Unfortunately, however, it was also concluded that the use of the lactic acid-glycolic acid bead dosage form was precluded from clinical usefulness in humans due to the incidence of tissue irritations of the naltrexone-containing beads. As further projected, it was thought that the results of this study would be useful in the development of an as yet unidentified, improved delivery system which is biocompatible and suitable for clinical use for the treatment of narcotic addiction.
See also, for example, CHIANG et al., "Implantable Narcotic Antagonists: A Possible New Treatment for Narcotic Addiction", Psychopharmacology Bulletin 21(3):672-675 (1985), also reporting the results of implantable naltrexone-containing beads or spheres composed of copolymers of lactic acid and glycolic acid, and which also concludes that the incidence of tissue irritation excludes clinical use of this bead dosage form.
In a recent CHIANG et al. study, "Medications development for the treatment of pregnant addicts and their infants", NIDA Research Monograph 149 (1995), bioerodible polymer technology involving implantable/injectable matrices to administer drugs are discussed. Again, despite attempts by several earlier studies (see ATKINS et al., "An injectable 30-day naltrexone delivery system", Proc. Intern Symp. Control Rel. Bioact. Mater 19:54 (1992); CHIANG et al. (1985) supra; MAA et al., "Controlled release of naltrexone pamoate from linear poly(ortho)esters", J. Controlled Rel. 14:21-28 (1990); ROSKOS et al., "A Morphine-Triggered Delivery System in the Treatment of Heroin Addiction", Clin. Mat. 13:109-119 (1993); and HELLER et al., "Recent developments in the synthesis and utilization of poly(ortho)esters", J. Control Release 16:3-14 (1991)), and others currently working on 30-day naltrexone delivery systems, none are clinically useful, and more research is necessary before a bioerodible drug delivery system for drug addiction can be commercialized.
The disappointing results of the CHIANG et al. studies ending in non-clinically useful subcutaneous dosage forms are not surprising in that adverse reactions of naltrexone leading to limited acceptance of the drug as a treatment for opiate-dependent persons had been earlier predicted. See HOLLISTER et al., "Adverse effects of Naltrexone in Subjects Not Dependent on Opiates", Drug and Alcohol Dependence, 8:37-41 (1981).
The CHIANG et al. naltrexone bead implants are further undesirable in that their manufacture is relatively complex and excessively costly.
Recently, U.S. Pat. No. 5,486,362 has disclosed a subcutaneous implantable drug delivery system said to useful for treating nicotine-addicted individuals which consists of a physical constraint modulation system ("PCMS") containing a drug substitute such as lobeline, a substituted piperidine compound obtained from dried leaves of the Indian tobacco herb Lobelia inflata. Lobeline is said to produce physiological effects similar to nicotine and thus is an effective nicotine substitute which assists individuals in lessening addiction to nicotine, albeit with some undesirable side effects. Other drug substitutes said to be deliverable include the opiate antagonist naltrexone. The PCMS system which contains and delivers the drug substitute is a biodegradable polymer suitable for subcutaneous injections, preferably microparticles suspended in a pharmaceutically acceptable vehicle just prior to subcutaneous injection to avoid the undesirable release of significant amounts of the drug substitute into the vehicle. Examples of polymers said to be preferred for use in the delivery system include poly(lactic/glycolic) and copolymers, which as shown above, have been found to be unacceptable forms for clinical delivery of naltrexone in the CHIANG studies.
In view of the above, an important need therefore exists for a time-lapse release of an antagonist which can be subcutaneously implanted in humans to provide therapeutic levels of antagonist to patients over extended periods of time to successfully treat various addictions.
An equally important need exists for a viable time-lapse release pharmaceutical delivery system which can also be subcutaneously implanted in humans or animals to provide therapeutic levels of pharmaceuticals or biologically active substances to patients over extended periods of time to treat a wide array of maladies or to deliver vitamins and/or nutraceuticals or other nutriments as desired.
Several devices attempting to fill this need have been reported but have not proved to be desirable and/or commercially reasonable for one or more reasons. For example, in U.S. Pat. No. 5,629,009 there is described a composition and method for the controlled release of certain water-soluble proteins which comprises a surface-eroding polymer matrix and a water-soluble bioactive factor(s)for the controlled administration of a bioactive substance to a local cell population. The composition is said to comprise a bio-erodible pharmasurface-eroding polymer having the bioactive substance interdispersed throughout a surface-eroding polymeric matrix, which erodes in the biological environment to release the bioactive substance to the selected area. The surface-eroding polymers is said to have hydrophobic backbones and hydrophillic hydrolytic linkages which bioerode from the surface at a constant rate in a biological environment, and can include polyanhydrides and polyorthoesters. Specific polyanhydrides can be poly-bis-p-carboxyphenoxypropane anhydride (PCPP) and poly-bis-p-carboxymethane anhydride (PCPM). Articles made according to this invention can include implants for dispensing a water-soluble bioactive factor to a local cell population.
In U.S. Pat. No. 5,021,241, there is described a solid sustained-release composition in the form of a needle-like, bar-like shape which is said to consist of an active ingredient in a pharmaceutically biodegradable carrier, such as proteins in the form of collagen, gelatin, and mixtures thereof. The compositions are said to be useful for injection or implanting in a body for release-sustaining of the active ingredient to maintain a desired level of the active ingredient in blood or in a lesional region for a long period of time. The pharmaceutically acceptable biodegradable carriers are limited to those which can be absorbed and are subject to enzymoloysis in the body. Active ingredients and may include medicaments which are effective in small amounts and wherein their activity is promoted by sustained release, and particularly those which are unstable to heat. Specific examples of the active ingredients are plasminogen activator, prostaglandin, prostacyclines, various by-hormones, interferons and interleukens, tissue necrosis factor and other cytokines.
These compositions are described as being prepared by mixing an aqueous solution of the active ingredient with a biodegradable carrier to incorporate the active ingredient in the carrier matrix, and then drying the mixture to a shaped product having enough strength for administering to a living body. Drying may be affected by, for example, allowing it to simply stand or by spray-drying. As further stated, by controlling the temperature of the solution at room temperature or lower, or by which the temperature of the active ingredient can be kept at room temperature or lower, the active ingredient is kept out of danger of being damaged by heat instability.
Next, in U.S. Pat. No. 4,897,268, there is described a method of delivering an active ingredient into an animal's system at a constant rate over a long period of time, such as one and one-half to six months or longer. The composition is stated as comprising a blend of free flowing spherical particles obtained by individually microencapsulating quantities of ingredient in different copolymer excipients which are biodegraded at varying rates. As also stated, an effective amount of a microencapsuled blend may be administered to the animal parenterally, e.g., intravenously, intramuscularly, subcutaneously, intranasally, intraperitoneally, or by inhalation. It is further stated that a quantity of the particles are of a particular co-polymer excipient in which the core active ingredient is released quickly after injection to deliver the ingredient after an initial period, and whereby a second quantity of the particles are of a type of excipient in which delivery of the encapsulated ingredient begins as the first quantity's delivery begins to decline with a third quantity of ingredient which is encapsulated with a still different excipient which results in delivery beginning as delivery of the second quantity begins to decline. Such is accomplished by varying a lactide/glycolide ratio in a poly(D,L-lactide-co-glycolide) encapsulation, or by utilizing a combination of various polymers with different lactide/glycolide ratios.
U.S. Pat. No. 3,887,699, there is described a drug dispensed in a biodegradable polymeric material that can be formed to a solid shape, which is said to exude the drug to the surface of a polymeric article, or otherwise the drug will migrate from the interior of the polymeric material to the surface until the surface is covered with a layer of the drug and an equilibrium is established between the surface layer and the drug at the interior of the polymeric material, whereby partially or totally removing the surface will disturb the equilibrium, and further amounts of drug will then permeate to the surface until the equilibrium is reestablished. This cycle is said to repeat itself until the supply of drug has been exhausted from the polymeric material.
Polymers useful in this device are said to be naturally occurring polymers such as sugar phosphates, which are known to be biodegradable, and synthetic polymers such as polylactides and polyglycolic acids, which are also biodegradable, i.e., that they are attacked and broken down into smaller chemical species by substances found in mammals, such as enzymes.
As further stated, lactic acid copolymers are said to offer a degree of flexibility in choosing the life of a polymer matrix, since such can be controlled through the amount and type of co-monomer used. Illustrated examples provided of suitable copolymers are glycolide, betapropiolactone, tetramethylglycolide, betabutyrolactone, tetramethylglycolide, b-butyrolactone, gammabutyrolactone, pivalolactone, intramolecular cyclic esters of alphahydroxybuteric acid, alphahydroxy, isovaleric acid, alphahydroxycaproic acid, alphahydroxy ethylbuteric acid, alphahydroxy isocaproic, alphahydroxy betamethyl valeric acid, alphahydroxy heptonic acid, alphahydroxy octanic acid, alphahydroxy deccanoic acid, alphahydroxy myristic acid, alphahydroxy stearic acid, alphahydroxy ligocenic acid, and betaphenol lactic acid. As also described, polyglycolic acids are said to provide excellent biodegradable properties. Drugs are incorporated in the biodegradable polymeric materials to form the drug delivery vehicle.
In U.S. Pat. No. 3,625,214 there is disclosed a drug-delivery device for the prolonged delivery of drugs for any predetermined time release mode, such as increased or decreased release, constant, pulsing, sinusoidal, etc. The device is said to be fabricated by applying a drug coating of a desired thickness to a drug-impermeable film which is soluble in body fluid to form a drug matrix coating. The coated film is then rolled to form a "jelly roll" configuration which upon administration to the body the outermost extremities of the film gradually erode in body fluids to expose drug coating, which is also soluble in body fluids, to release the drug to body tissues. Different designs of the "drug spiral" are said to account for variable release modes. Drugs useful in this device include proteins such as insulin, desensitizing agents such as ragweed pollen antigens, hay fever, pollen antigens, dust and milk antigens, various vaccines such as smallpox, yellow fever, cholera, and scarlet fever, various antibiotics such as penicillin, tetracycline, nystatin and streptomycin, and sedatives such as sodium pentobarbital phenobarbital, and other drugs having the same or different physiological activity as above-mentioned.
Film or carrier materials are said to be preferably polymeric in nature, inclusive of gelatins, collagen, polyvinyl alcohol, or polybasic, linear, dibasic acid anhydrides of this formula: ##STR1##
such as polyanhydride polymers of sebacic and azelaicacides, polyhydroxyacedic acids and poly sulfite polymers, or polymers that are cleaved by enzymes present in body fluids such as chitin which is enzymatically cleaved by lysozyme. The polyanhydride polymers are further described as being prepared by condensing respective dibasic acids in the presence of SOCL.sub.2, benzene and ethyl acetate.
As also discussed these drug-delivery devices can be administered by implants, suppository, peroral pellets, oral bolus, vaginal pessary, buccal or sublingual lozenge, or ocular inserts.
Other prolonged-action pharmaceutical administration is discussed, for example, in Remington's Pharmaceutical Sciences, pp. 5094 et. seq. (1980). In this reference products are described as having properties of "sustained release", "prolonged action", and "repeat action". As discussed for example on page 1602, despite the fact that the taking of drugs by parenteral routes of administration is commonplace and many millions of dollars worth of parenteral products are sold annually for use in man there has been very little good research performed on the factors effecting absorption of drugs from parenteral sites of administration. This article also discusses the development and use of direct pellets in medical practice, and physical factors that have been suggested to effect implanted drug absorption rates including, inter alia, pellet density (hardness), crystal size used in making the pellet, and the influence of diluents. As further discussed, the densities of pellets made of pure drug depend upon factors such as the compression pressure used in making the pellets since absorption rates are directly proportional to the area of the pellet exposed to body fluids; other experiments are said to have shown that crystal size used in the manufacture of pure drugs have no effect in pellet absorption rates. As also stated, while pellet density and the size of the crystals used in pellet manufacture apparently have no effect on absorption rates the addition of a diluent to the formulation does have an effect. There are also many types of diluents and their modes of action are different in either enhancing or retarding drug absorption from implants. Unfortunately, as also mentioned, there are no general rules available for predicting absorption rates of a given drug diluent mixture, and thus there is no expectation of a successful implant over a given time period available, as such must be tested through trial and error.
In YOLLES et al., "Time-Release Depot for Anti-Cancer Patients", General Pharmaceutical Sciences, Vol. 64, Number 1, (January 1975) pp. 115 to 116, the controlled release of narcotic antagonist from composites made with poly (lactic acid) in film and in particle form is discussed. This paper undertakes an investigation to determine in vivo experiments of the amount of release of two particular anticancer agents from poly (lactic acid) composites. As shown hereinabove, however, in Chiang et al., implanted narcotic used in conjunction with beads and spheres composed of lactic acid co-polymers have been found unacceptable for use clinically.
Also, see for example, in YOLLES et al., "Long acting delivery systems for narcotic antagonists." Journal of Pharmaceutical Sciences, Vol. 64, No. 2, pp. 348-349 (February 1975), again discussing release rates of naltrexone from poly (lactic acid) composites.
Further, see WOODLAND et al., "Long-Acting Delivery Systems for Narcotic Antagonist", Journal of Medicinal Chemistry, Vol. 16, No. 8, pp. 897-901 (1973). This reference discusses composites of radioactive cyclazocine (2-cyclopropyl methyl-2 prime-hydroxide-5,9-dimethyl-6,7-benzomorphan) with films of composite materials containing poly (lactic acid) of molecular weights ranging between 45,000 thousand and 70,000 thousand, to provide composites capable of releasing the drug cyclazocine for upwards of two months.
In YOLLES et al., "Controlled-Release of Biologically Active Drugs", Bulletin of the Parenteral Drug Association, Vol. 30, No.6, pp. 306 through 312, (November-December 1976) there is discussed a system of delivery of drugs at a controlled rate of a long period of time, perhaps months, which comprises the incorporation of a drug and a polyometric matrix and shaping the composite into a form such as a film, pellet or chip, and then implanting the structure into the body tissue of animals by surgery or hypodermic injection. The release rates, in vivo and in vitro, of progesterone, estradiol and three narcotic antagonist conclusive cyclazocine, naloxone, and naltrexone and two anticancer are studied. The polymer composites are again of non-desirable polylactic acid composition.
LEAFE et al., "Injection Method For Delivery of Long-Acting Narcotic Antagonist", Advances in Biochemical Psychopharmacology, Vol. 8., No. 74, pp. 569-575 (Raven Press, New York, N.Y.) describes the hypodermic injection of a composite of cyclazocine-poly(lactic acid). In these tests the composite was hypodermically injected as a inspersion in carboxymethyl cellulose into the body tissue of rats.
In Yolles, "A Psychiatrist Looks at Drug Abuse" Industrial Medicine, Vol. 41, No. 10, pages 29-35 (October 1972), drug abuse and addiction in general are discussed. See further, YOLLES et al., "Time Released Depo for Anticancer Agents", Acta Pharm. Swec., Vol. 15, pp. 382-388 (1978) discussing composites containing poly (lactic acid) and several anticancer agents; Yolles, "Time-Release Depo for Anticancer Drugs: Release of Drug Covalently Bonded to Polymers", Journal of a Parenteral Drug Association, Vol. 32, No. 4, (July-August 1978), discussing composites containing poly(lactic acid) and anticancer agents, namely cis dyeamine platinum (II), cyclophosphine, and dioxorubins; and Yolles, "Controlled Release of Biologically Active Agents", Polymer Science and Technology, Vol. 8, pages 245-261 (Plenum Press New York, N.Y. 1975) discussing the development of injectable systems for sustained delivery of drugs at controlled rates inclusive of release rates of naloxone and naltrexone, progesterone, and two anticancer drugs prepared by manufacturing composites of polymer (polyethylene or polylactic acid) and a plasticizer (tributal citrate), and melt pressing these composites into sheets containing a mixture of the drug and the polymer.
To date, none of the aforementioned drug delivery devices have been shown to be clinically useful and/or commercially viable.